Blood-based gene expression as a biodosimetry model for neuroblastoma patients treated with ¹³¹I-mIBG Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/r207ts143

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  • Internal dosimetry is challenging and relies on estimates using MIRD or ICRP biokinetic models. To address this, we looked at gene expression analysis in whole blood from radiotherapy patients. Patients with relapsed or refractory neuroblastoma who received ¹³¹I-mIBG at UCSF were used to correlate internal ionizing radiation (IR) dose with selected gene expression. 40 patients, median age 7 years, had blood drawn at baseline, 72, 96, and 120 hours after ¹³¹I-mIBG infusion. A total of 14 patients received mIBG treatment only, while 19 patients received Irinotecan and 7 received Vorinostat in combination with mIBG. Whole body absorbed dose was calculated for each patient based on the mIBG treatment doses using MIRD internal dosimetry models. Two models were used and compared with the decision being to use a model that was predictive based on an average of three patient’s responses. We then assessed transcripts using RT-PCR that were the most significant for describing the mixed therapeutic treatments over time. Modulation was evaluated statistically using multiple regression analysis for data at hours 0, 72, 96. A total of 6 genes were analyzed across 40 patients: CDKN1A, FDXR, GADD45A, BCLXL, STAT5B, and BAX. Four genes were significantly modulated upon exposure to ¹³¹I-mIBG at 72 hours, as well as at 96 hours, when controlling for dose and chemotherapy. Five genes showed significant responses to Irinotecan combined with mIBG and 2 had significant responses to Vorinostat combined with mIBG, all when controlling for time and dose. A model was then developed to predict absorbed dose based on modulation of gene transcripts within white blood cells. This study represents a unique effort of using radiotherapy patients to characterize biomarkers that may be useful for biodosimetry and treatment. Our data indicates that transcripts, which have been previously identified as biomarkers of external exposures in ex vivo whole blood and in vivo radiotherapy patients, are also good indicators of internal exposure over time. The characterization of internal irradiation-responsive genes will provide valuable understanding of the genetic mechanisms related to internal exposures.
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  • description.provenance : Approved for entry into archive by Laura Wilson(laura.wilson@oregonstate.edu) on 2014-07-30T16:25:33Z (GMT) No. of bitstreams: 2 license_rdf: 1223 bytes, checksum: d127a3413712d6c6e962d5d436c463fc (MD5) EdmondsonDavidA2014.pdf: 1110396 bytes, checksum: c7a93a922417005fd5eb777fae09e16a (MD5)
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